Heparin, more specifically described as a glycosaminoglycan, is a polysaccharide that resides almost exclusively in mast cells. Its physiologic purpose, however, remains uncertain, although roles in neovascularization and in the inflammatory response appear likely. Clearly, endogenous heparin plays no significant role in maintaining the fluidity of circulating blood. Heparan, a related glycosaminoglycan having a substantially lower sulfur content, dangles tantalizingly from endothelial cell membranes to attract circulating antithrombin III (ATIII) irresistibly and potentiate thrombin inhibition. Physiologic anticoagulation at the blood-tissue interface thereby derives not from heparin but from heparan. The primary physiologic purpose of heparin may be to participate in nonimmunologic defense against bacterial infections, with other roles likely in capillary angiogenesis and lipid metabolism.

Most heparin preparations can be described as unfractionated, which means that the heparin compound isolated from animal tissues contains heparin molecules of various lengths, with molecular weights ranging from 3,000 to more than 40,000 Da. The mean molecular mass approximates 15,000 Da (7,8) (Fig. 19.1). The molecular weight distribution varies somewhat with the tissue source, animal source, and method of purification (9,10). This variability has some clinical relevance because the spectrum of clinical actions of heparin derives in part from the molecular weight distribution of a heparin compound (11). As a result, each unfractionated commercial heparin preparation might best be described as a family of drugs with actions and potency that may vary from batch to batch (12,13,14).

Heparin can be distinguished from other polysaccharides by its acid nature. It is the strongest macromolecular acid in the body, a characteristic that derives from abundant sulfation of its saccharide units. The basic subunit consists of a repeating disaccharide that contains a uronic acid residue linked to a glucosamine residue (Fig. 19.2). Both the uronic acid and glucosamine residues can assume many different forms based on the side groups attached to these hexose units. Sulfate groups may attach to the hexose ring through an oxygen, amino, aminoacetyl, or methane link. The result is a large molecule that bears a highly negative charge within the physiologic pH range, and that therefore attracts positively charged molecules. Specific saccharide sequences along the heparin chain determine binding sites to other macromolecules for which it has high affinity, such as ATIII, thrombin, and lipoprotein lipase. In the case of ATIII, a specific pentasaccharide sequence binds consistently to a specific amino acid sequence on the ATIII molecule (15).

Heparin can be purified from several tissues and from several mammalian species. Although the name heparin was selected because the substance was originally isolated from liver extracts, intestinal mucosa and lung tissue represent the most common commercial sources. Mucosal heparin tends to have a lower mean molecular weight, a more cross-linked polysaccharide structure, and a lower cost than lung heparin (12). Differences in the tissue source from which heparin is extracted influence molecular structure and activity more than differences in the animal source (16,17). However, nuclear magnetic resonance spectroscopy has enabled the identification of differences between porcine and bovine mucosal heparin in sulfation of various subunits. Nuclear magnetic resonance spectroscopy has also demonstrated a higher content of 3-O-sulfated glucosamine units (active site for ATIII binding) in porcine than in bovine mucosal heparin (18). Heparin manufacturers most often extracted mucosal heparin from pigs (porcine mucosal heparin) and lung heparin from cattle (bovine lung heparin).

Both porcine mucosal heparin and bovine lung heparin had been widely used as anticoagulants for CPB. Both provide effective anticoagulation and prevent thrombosis in experimental models (19) and in adult volunteers (20). Investigating standardized needle punctures in exposed carotid arteries in dogs, Abbott et al. (21) found a higher incidence of delayed hemorrhage in animals anticoagulated with mucosal heparin than with lung heparin. This difference remained significant even when the anticoagulation was neutralized with protamine. Two studies prospectively compared mucosal and lung heparin for CPB in humans. Stewart and Gaich (22) found that higher doses of mucosal heparin than of lung heparin were needed to reach the desired prolongation of the activated clotting time (ACT), a finding that might be attributable to batch variability. In a dialysis study comparing mucosal with lung heparin at standard patient doses of heparin, a lower anticoagulant activity was noted in International Units/mL with bovine heparin, despite higher weight-based drug levels. Both preparations resulted in anticoagulant effects and plasma levels within the recommended safe range (23). Fiser et al. (24) observed greater postoperative blood loss in patients randomly assigned to receive mucosal heparin than in those who received lung heparin. Both animal and human studies indicate that mucosal heparin can be neutralized with 25% to 30% less protamine than can lung heparin, a consequence of the lesser anti-IIa activity of mucosal heparin than bovine (17,25). These studies used standard tests of plasma coagulation such as clotting time and activated partial thromboplastin time (aPTT), which might not detect residual unneutralized inhibition of factor Xa. Because of its lower mean molecular weight, mucosal heparin, in concert with ATIII, more effectively inhibits factor Xa than does lung heparin (26), and protamine only partially neutralizes this effect. The higher mean molecular weight of lung heparin enables this molecule to inhibit factor IIa more effectively through ATIII. The anti-IIa activity is more susceptible to protamine antagonism, which may explain the greater propensity for delayed bleeding found after anticoagulation with mucosal heparin (20,22) and the requirement for lower doses of protamine for neutralization. Fairly limited prospective comparisons and some theoretic considerations therefore suggest a slight advantage of lung heparin for CPB anticoagulation, but many hospitals have ceased to utilize lung heparin because of its greater propensity for HIT. In the mid-1990s, bovine heparin production and commercialization ceased in the United States and many European countries due to fears of potential transmission of bovine spongiform encephalopathy. Porcine heparin became the exclusive heparin product used in medicine, hemodialysis, and cardiac surgery. Porcine heparin is primarily derived from Chinese production sources, and the reliance on a single source of drug is very limiting and increases the risk of drug shortage. This became evident in 2008
when the heparin produced in China was found to be contaminated with oversulfated chondroitin sulfate, and was responsible for catastrophic hypotensive events in cardiac surgery and hemodialysis patients. A serious heparin shortage ensued as there were no other manufacturers making heparin in the quantities being produced by China. In addition, current detection methods for transmissible BSE agents are superior now compared with those during the mid-1990s (when mad cow disease reached crisis numbers), and some believe that a reintroduction of bovine heparin into the US commercial market is in order. Both clinical studies and practice demonstrate that for CPB anticoagulation, clearly both mucosal and lung heparin are effective and safe.

Because of the acid nature of heparin, a ligand must be bound to it when the compound is prepared for commercial use. Sodium and calcium have been used for this purpose. The two salts are indistinguishable with intravenous heparin administration, but the calcium salt retards the uptake of subcutaneously administered heparin (9,27) and may reduce local hematoma formation with subcutaneously administered heparin.

Four assays have been used in recent years to determine the potency of unfractionated heparin (UH) (19,28), including International, United States, British, and European standards. The International Standard represents the mean of the pharmacopoeial methods, which results in some variation in potency between international units (IU) and United States Pharmacopoeia (USP) units. The USP assay defines 1 USP unit as the amount of heparin that maintains the fluidity of 1 mL of citrated sheep plasma for 1 hour after recalcification. The
British Pharmacopoeia (BP) method uses sulfated ox blood activated with thromboplastin. The BP method has been superseded by a European Pharmacopoeia (EP) method, which recalcifies sheep plasma in the presence of kaolin and cephalin incubated for 2 minutes, thereby constituting an aPTT for sheep plasma. The EP method rigorously standardizes the collection of sheep plasma, which might diminish the assay variability previously reported between batches of sheep plasma substrate (16). Although speculation exists about the clinical significance of batch-to-batch variability in heparin potency, it seems more likely that pharmacodynamic differences account for most of the observed variations in the clinical anticoagulation response to heparin (see subsequent section on Heparin Resistance). Because the relation between mass (milligrams) and potency (units) varies among heparin preparations, it appears more sensible to record heparin doses in units than in milligrams.

Because heparin administration for CPB is exclusively intravenous, this discussion is limited to that route of administration. After central venous injection of a heparin bolus, the onset of maximal ACT prolongation in the radial artery occurs within 1 minute. A previous study (29) suggested that heparin action peaks 10 to 20 minutes after administration in cardiac surgical patients, but this finding probably was an artifact representing prolongation of the ACT by other factors, such as hemodilution and hypothermia. Controlling for these factors, another study clearly demonstrated that the onset of action of heparin is much faster, and maximal ACT prolongation probably occurs in less than 5 minutes (30). A rapid redistribution effect probably accounts for a modest reduction in the anticoagulant effect of heparin that occurs 3 to 13 minutes after the peak effect (Fig. 19.3). It remains possible that the onset of action would be slightly delayed in states of low cardiac output or with peripheral venous injection.

Heparin is macromolecular and highly polarized, so one would expect minimal distribution beyond the bloodstream. These principles and the results of bioassay studies of heparin kinetics were the basis for the former belief that the distribution of heparin is virtually confined to the plasma compartment of the bloodstream (31,32). Substantial in vitro evidence now points to the redistribution of heparin into the endothelial cells (33,34,35,36), although this redistribution appears small in comparison with that of most other drugs. Uptake into extracellular fluid, alveolar macrophages, splenic and hepatic reticuloendothelial cells, and vascular smooth muscle also occurs (37,38,39). Some or all of these tissues create a relatively small reservoir for heparin that probably contributes to the delayed recurrence of heparin-induced anticoagulation (heparin rebound) after protamine neutralization of the heparin residing in the bloodstream. Defining an apparent volume of distribution for heparin remains elusive because pharmacokinetic studies in humans have used some measure of heparin effect (i.e., a bioassay) rather than direct measurement of plasma heparin concentration. Bioassays represent the most practical approach to the clinical evaluation of heparin pharmacodynamics, but these assays can only indirectly and crudely assess pharmacokinetics.

Heparin elimination has been studied by using various clotting times as bioassays, so the available information largely defines the time course of its clinical activity. The clotting times differ in their sensitivities to heparin, so differences reported in heparin “elimination” kinetics under similar conditions are not necessarily inconsistent. Despite these unavoidable limitations, several aspects of heparin pharmacokinetics can be explained by existing studies. Very small doses of heparin produce minimal or no effect, suggesting a rapid initial clearance, possibly the result of the affinity of heparin for endothelial membranes (40). The doses used for CPB anticoagulation are very large, and the biologic elimination half-life of heparin is dose-dependent (41,42). In the only volunteer study in which doses sufficient for CPB were used, Olsson et al. (41) found a half-life of 126 ± 24 minutes with a heparin dose of 400 units/kg. The half-lives for doses onefourth and one-half that large were 61 ± 9 and 93 ± 6 minutes, respectively. Because CPB distorts the bioassay methods
through hypothermia and hemodilution, attempts to define heparin pharmacokinetics in patients undergoing CPB are largely impractical. Hypothermia delays heparin elimination, with virtually constant heparin concentrations shown during 40 to 100 minutes of CPB at 25°C (43). Wright et al. (44) found a progressive decline in heparin concentrations at all temperatures, but the rate of decline was delayed in proportion to the hypothermia. Bull et al. (45) found a small decrease in the rate of ACT decline at 30°C (in comparison with normothermia), although the independent prolongation of ACT by hypothermia had not been discovered at the time of that study. Mabry et al. (46) found the consumption of heparin to vary from 0.01 to 3.86 units/kg/min during CPB. In addition, there is little correlation between the initial ACTbased sensitivity to heparin and the rate of heparin decay (47). In children, the variability in ACT response is greater than that in adults and is highly dependent on the test mechanism and activators used (48) (Fig. 19.4).

Severe renal impairment may also prolong heparin action, although available studies yield conflicting results. Liver disease apparently has little effect on heparin elimination. The primary mechanism for heparin elimination remains uncertain, but metabolism in the reticuloendothelial system and renal elimination both occur (37,39,40).

Plasma coagulation, the formation of a platelet plug, and fibrinolysis constitute the three major components of blood clot formation and dissolution. The therapeutic effects of heparin derive primarily from its effects on plasma coagulation, described in the preceding text, but heparin also affects the other two components.

Heparin-induced activation of fibrinolysis has been identified in a primate model (62). During simulated CPB in a
baboon model, heparin administration led to activation of fibrinolysis as measured by plasmin activity, immunoreactive plasmin light chain, and immunoreactive fibrinogen fragment E (63). The mechanism whereby heparin facilitates fibrinolysis may involve the direct stimulation of plasminogen activator release from endothelial cells and monocytes. Additional modes of activation include indirect stimulation of plasminogen activator by release of protein C, inhibition of fibrin polymerization (64), modulation of antiplasmin effects, and enhancement of the effects of tissue factor pathway inhibitor (TFPI). Activation of the fibrinolytic pathway does occur during anticoagulation associated with CPB, so heparin might participate in this activation.

Heparin also has numerous effects on platelets, many of which occur acutely, and these would therefore be relevant in patients undergoing CPB. Table 19.1 lists the aggregatory effects of heparin on platelets, which most often represent laboratory findings obtained in human platelet-rich plasma. The clinical significance of these findings is uncertain, but clearly heparin binds avidly to platelets. With the use of specific chemical and enzymatic treatments to produce heparin-derived glycosaminoglycans, the platelet-binding properties of heparin have been elucidated (77). Although specific receptors for heparin on the platelet surface have not been identified, heparin binding relates directly to molecular weight and sulfation and is unrelated to ATIII affinity (77,78,79,80,81). Heparin binding decreases with the decreasing size of the heparin fragment and is therefore clinically negligible in the low-molecular-weight heparin (LMWH) preparations. Small quantities of heparin may bind to the GPIIb/IIIa platelet receptor, but this is not the major locus for heparin binding. At clinical doses, heparin induces a platelet release reaction characterized by release of platelet factor 4 (PF4), GPIIb/IIIa activation, P-selectin expression, and increased aggregation that is not seen with LMWH derivatives (75,82). At plasma levels as high as 100 units/mL, heparin suppresses degranulation and P-selectin expression, a finding that indicates the future possibility of separation of the anticoagulant and the antiplatelet properties of heparin (76,83). Moderate prolongation of bleeding time and transient decreases in platelet count have been present in some investigations and absent in others (80). Both predictable and idiosyncratic effects of heparin on platelets have been reviewed by Warkentin and Kelton (80). The idiosyncratic syndrome of HIT is discussed later in a separate section (see Heparin-Induced Thrombocytopenia).

In clinical settings other than CPB, bleeding complications comprise the most common side effect of heparin, with reported incidences varying from 1% to 37% (84,85,86,87). The profound anticoagulation present during CPB probably increases surgical bleeding, but blood salvage through the cardiotomy suction usually renders this unimportant. Large doses of heparin induce fibrinolysis and activate platelet activation to contribute to abnormalities of hemostasis (88). Conversely, insufficient heparin anticoagulation during CPB causes consumption of coagulation factors, which may also result in a bleeding diathesis (89). Excessive postoperative bleeding from residual unneutralized heparin or from heparin rebound can occur after CPB and should be closely monitored (see Chapter 20).

The intravenous heparin bolus dose administered before CPB decreases arterial pressure and systemic vascular resistance approximately 10% to 20% without affecting cardiac output or heart rate (90,91). Urban et al. (91) related this change to a decrease in ionized calcium levels, and they were able to prevent them by prophylactically administering 125 mg of calcium chloride.

Heparin can induce a variety of metabolic and immunologic effects (92) that might contribute to the array of abnormalities known to occur in those systems during CPB. Heparin dramatically increases plasma levels of lipoprotein lipase by releasing this enzyme from vascular endothelium. This activity bears no relation to ATIII affinity, and it results in triglyceride degradation and increased circulating levels of free fatty acids. Although the clinical significance of these effects remains unclear, they could potentially affect myocardial metabolism and the plasma-free fraction of lipid-soluble drugs.

Rare acute reactions attributed to heparin include anaphylaxis, pulmonary edema (93,94,95,96,97,98,99), and disseminated intravascular coagulation (100). Some of these reactions have been traced to the preservatives chlorocresol and chlorbutol (95,96). Harada et al. (93) reported the uneventful use of bovine lung heparin for CPB in a child who had previously experienced anaphylaxis from porcine mucosal heparin, and
Schey (101) reported resolution of a localized skin reaction to subcutaneous heparin injections when LMWH was substituted for UH. Interactions with antibiotics have also been reported, notably with gentamicin and erythromycin (102,103), although these appear unlikely to have clinical significance. Administration of heparin for weeks to months has been associated with osteoporosis, alopecia, hyperaldosteronism, and benign elevation of serum glutamic oxaloacetic transaminase levels (104,105,106).

Once Bull et al. (45

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